2-(Phenyl)-2h-pyrazole-3-carboxylic acid-n-4-(thioxo-heterocyclyl)-phenyl-amide derivatives and corresponding imino-heterocyclyl derivatives and relates compounds for use as inhibitors of the coagulation factors xa and/or viia for treating thromboses

ABSTRACT

The invention relates to the novel compounds of formula (I), wherein D, M, W, X, Y, T, R 1  and R 1 ′ are defined as in patent claim 1. The inventive compounds are inhibitors of coagulation factor Xa and can be used in the prophylaxis and/or therapy of thromboembolic diseases and in the treatment of tumors.

The invention relates to compounds of the formula I

in which

-   -   D is absent or        -   is a saturated, fully or partially unsaturated 3- to            4-membered alkylene chain, in which from 1 to 3 carbon atoms            may be replaced by N and/or 1 or 2 carbon atoms may be            replaced by 1 or 2 O and/or 1 or 2 S atoms, but where at            most up to 3 carbon atoms are replaced and where, in            addition, the alkylene chain and/or a nitrogen present            therein may be monosubstituted, disubstituted or            trisubstituted by Hal, A, —[C(R³)₂]_(n)-Ar,            —[C(R³)₂]_(n)-Het, —[C(R³)₂]_(n)-cycloalkyl, OR², N(R²)₂,            NO₂, CN, COOR², CON(R²)₂, NR²COA, NR²SO₂A, COR², SO₂NR²            and/or S(O)_(m)A, and where, furthermore, one CH₂ group in            the alkylene chain may also be replaced by a C═O group,    -   M is a phenyl ring or an aromatic heterocyclic ring, which may        contain 1-2 N, O and/or S atoms,    -   R¹ and R¹′ are each, independently of one another, H, Hal, A,        OR², N(R²)₂, NO₂, CN, COOR², CON(R²)₂, C(═S)N(R²)₂,        —[C(R³)₂]_(n)-Ar, —[C(R³)₂]_(n)-Het, —[C(R³)₂]_(n)-cycloalkyl,        —[C(R³)₂]_(n)—N(R³)₂, CN, —C(═NH)—NH₂ which is unsubstituted or        monosubstituted by C(═O)R³, COOR³, OR³, OCOR³, OCOOR³ or by a        conventional amino-protecting group, or    -   R² is H, A, —[C(R³)₂]_(n)-Ar, —[C(R³)₂]_(n)-Het,        —[C(R³)₂]_(n)-cycloalkyl, —[C(R³)₂]_(n)—N(R³)₂ or        —[C(R³)₂]_(n)—OR³,    -   R²′ is H, A, —[C(R³)₂]_(n)—Ar′, —[C(R³)₂]_(n)-Het′,        —[C(R³)₂]_(n)-cycloalkyl, —[C(R³)₂]_(n)—N(R³)₂ or        —[C(R³)₂]_(n)—OR³,    -   R²″ is H, A, —[C(R³)₂]_(n)-Ar′, —[C(R³)₂]_(n)-cycloalkyl,        —[C(R³)₂]_(n)—N(R³)₂ or —[C(R³)₂]_(n)—OR³,    -   R³ is H or A,    -   W is a monocyclic or bicyclic saturated, unsaturated or aromatic        carbocyclic or heterocyclic ring having from 1 to 4 N, O and/or        S atoms, which may be monosubstituted or disubstituted by R²,    -   X is CONR², CONR²C(R³)₂, —C(R³)₂NR², —C(R³)₂NR²C(R³)₂,        —C(R³)₂O—, —C(R³)₂OC(R³)₂— or NR²CO,    -   Y is alkylene, cycloalkylene, Het-diyl or Ar-diyl,    -   T is a monocyclic or bicyclic, saturated, unsaturated or        aromatic carbocyclic or heterocyclic ring having from 1 to 4 N,        O and/or S atoms which is monosubstituted or disubstituted by        ═S, ═NR², ═N—CN, ═N—NO₂, ═NOR², ═NCOR², ═NCOOR² or ═NOCOR² and        may furthermore be monosubstituted, disubstituted or        trisubstituted by Hal, A, —[C(R³)₂]_(n)-Ar, —[C(R³)₂]_(n)-Het,        —[C(R³)₂]_(n)-cycloalkyl, OR³, N(R³)₂, NO₂, CN, COOR², CON(R²)₂,        NR²COA, NR²CON(R²)₂, NR²SO₂A, COR², SO₂NR² and/or S(O)_(m)A,    -   A is unbranched or branched alkyl having 1-10 carbon atoms, in        which one or two CH₂ groups may be replaced by O or S atoms        and/or by —CH═CH— groups, and/or in addition 1-7H atoms may be        replaced by F,    -   Ar is phenyl, naphthyl or biphenyl, each of which is        unsubstituted or monosubstituted, disubstituted or        trisubstituted by Hal, A, OR³, N(R³)₂, NO₂, CN, COOR³, CON(R³)₂,        NR³COA, NR³CON(R³)₂, NR³SO₂A, COR³, SO₂N(R³)₂, S(O)_(m)A,        —[C(R³)₂]_(n)—COOR²′ or —O—[C(R³)₂]_(o)—COOR²′,    -   Ar′ is phenyl or benzyl, each of which is unsubstituted or        monosubstituted or disubstituted by Hal,    -   Het is a monocyclic or bicyclic, saturated, unsaturated or        aromatic heterocyclic ring having from 1 to 4 N, O and/or S        atoms, which may be unsubstituted or monosubstituted,        disubstituted or trisubstituted by carbonyl oxygen, ═S, ═N(R³)₂,        Hal, A, —[C(R³)₂]_(n)-Ar, —[C(R³)₂]_(n)-Het¹,        —[C(R³)₂]_(n)-cycloalkyl, —[C(R³)₂]_(n)—OR²′,        —[C(R³)₂]_(n)—N(R²′)₂, NO₂, CN, —[C(R³)₂]_(n)—COOR²′,        —[C(R³)₂]_(n)—CON(R²′)₂, —[C(R³)₂]_(n)—NR²′COA, NR²′CON(R²′)₂,        —[C(R³)₂]_(n)—NR²′SO₂A, COR²′, SO₂NR²′ and/or S(O)_(m)A,    -   Het¹ is a monocyclic or bicyclic, saturated, unsaturated or        aromatic heterocyclic ring having 1 or 2 N, O and/or S atoms,        which may be unsubstituted or monosubstituted or disubstituted        by carbonyl oxygen, ═S, ═N(R³)₂, Hal, A, OR²″, N(R²″)₂, NO₂, CN,        COOR²″, CON(R²″)₂, NR²″COA, NR²″CON(R²″)₂, NR²″SO₂A, COR²″,        SO₂NR²″ and/or S(O)_(m)A,    -   Hal is F, Cl, Br or I,    -   n is 0, 1 or 2,    -   m is 0, 1 or 2,    -   o is 1, 2 or 3,        and pharmaceutically usable derivatives, solvates and        stereoisomers thereof, including mixtures thereof in all ratios.

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

It has been found that the compounds of the formula I and salts thereofhave very valuable pharmacological properties and are well tolerated. Inparticular, they exhibit factor Xa-inhibiting properties and cantherefore be employed for combating and preventing thromboembolicdisorders, such as thrombosis, myocardial infarction, arteriosclerosis,inflammation, apoplexia, angina pectoris, restenosis after angioplastyand claudicatio intermittens.

The compounds of the formula I according to the invention mayfurthermore be inhibitors of the coagulation factors factor VIIa, factorIXa and thrombin in the blood coagulation cascade.

Aromatic amidine derivatives having an antithrombotic action aredisclosed, for example, in EP 0 540 051 B1, WO 98/28269, WO 00/71508, WO00/71511, WO 00/71493, WO 00/71507, WO 00/71509, WO 00/71512, WO00/71515 and WO 00/71516. Cyclic guanidines for the treatment ofthromboembolic disorders are described, for example, in WO 97/08165.Aromatic heterocyclic compounds having a factor Xa inhibitory activityare disclosed, for example, in WO 96/10022. SubstitutedN-[(aminoiminomethyl)phenylalkyl]azaheterocyclylamides as factor Xainhibitors are described in WO 96/40679. Pyrazole derivatives aredisclosed in WO 01/29006 and WO 02/24690.

The antithrombotic and anticoagulant effect of the compounds accordingto the invention is attributed to the inhibitory action againstactivated coagulation protease, known by the name factor Xa, or to theinhibition of other activated serine proteases, such as factor VIIa,factor IXa or thrombin.

Factor Xa is one of the proteases involved in the complex process ofblood coagulation. Factor Xa catalyses the conversion of prothrombininto thrombin. Thrombin cleaves fibrinogen into fibrin monomers, which,after crosslinking, make an elementary contribution to thrombusformation. Activation of thrombin may result in the occurrence ofthromboembolic disorders. However, inhibition of thrombin may inhibitthe fibrin formation involved in thrombus formation.

The inhibition of thrombin can be measured, for example by the method ofG. F. Cousins et al. in Circulation 1996, 94, 1705-1712.

Inhibition of factor Xa can thus prevent the formation of thrombin. Thecompounds of the formula I according to the invention and their saltsengage in the blood coagulation process by inhibiting factor Xa and thusinhibit the formation of thrombuses.

The inhibition of factor Xa by the compounds according to the inventionand the measurement of the anticoagulant and antithrombotic activity canbe determined by conventional in-vitro or in-vivo methods. A suitablemethod is described, for example, by J. Hauptmann et al. in Thrombosisand Haemostasis 1990, 63, 220-223.

The inhibition of factor Xa can be measured, for example by the methodof T. Hara et al. in Thromb. Haemostas. 1994, 71, 314-319.

Coagulation factor VIIa initiates the extrinsic part of the coagulationcascade after binding to tissue factor and contributes to the activationof factor X to give factor Xa. Inhibition of factor VIIa thus preventsthe formation of factor Xa and thus subsequent thrombin formation.

The inhibition of factor VIIa by the compounds according to theinvention and the measurement of the anticoagulant and antithromboticactivity can be determined by conventional in-vitro or in-vivo methods.A conventional method for the measurement of the inhibition of factorVIIa is described, for example, by H. F. Ronning et al. in ThrombosisResearch 1996, 84, 73-81.

Coagulation factor IXa is generated in the intrinsic coagulation cascadeand is likewise involved in the activation of factor X to give factorXa. Inhibition of factor IXa can therefore prevent the formation offactor Xa in a different way.

The inhibition of factor IXa by the compounds according to the inventionand the measurement of the anticoagulant and antithrombotic activity canbe determined by conventional in-vitro or in-vivo methods. A suitablemethod is described, for example, by J. Chang et al. in Journal ofBiological Chemistry 1998, 273, 12089-12094.

The compounds according to the invention may furthermore be used for thetreatment of tumours, tumour illnesses and/or tumour metastases. Acorrelation between tissue factor TF/factor VIIa and the development ofvarious types of cancer has been indicated by T. Taniguchi and N. R.Lemoine in Biomed. Health Res. (2000), 41 (Molecular Pathogenesis ofPancreatic Cancer), 57-59.

The publications listed below describe an antitumoural action of TF-VIIand factor Xa inhibitors for various types of tumour:

-   K. M. Donnelly et al. in Thromb. Haemost. 1998; 79: 1041-1047;-   E. G. Fischer et al. in J. Clin. Invest. 104: 1213-1221 (1999);-   B. M. Mueller et al. in J. Clin. Invest. 101: 1372-1378 (1998);-   M. E. Bromberg et al. in Thromb. Haemost. 1999; 82: 88-92

The compounds of the formula I can be employed as medicament activeingredients in human and veterinary medicine, in particular for thetreatment and prevention of thromboembolic disorders, such asthrombosis, myocardial infarction, arteriosclerosis, inflammation,apoplexia, angina pectoris, restenosis after angioplasty, claudicatiointermittens, venous thrombosis, pulmonary embolism, arterialthrombosis, myocardial ischaemia, unstable angina and strokes based onthrombosis.

The compounds according to the invention are also employed for thetreatment or prophylaxis of atherosclerotic diseases, such as coronaryarterial disease, cerebral arterial disease or peripheral arterialdisease. The compounds are also employed in combination with otherthrombolytic agents in myocardial infarction, furthermore forprophylaxis for reocclusion after thrombolysis, percutaneoustransluminal angioplasty (PTCA) and coronary bypass operations.

The compounds according to the invention are furthermore used for theprevention of rethrombosis in microsurgery, furthermore asanticoagulants in connection with artificial organs or in haemodialysis.

The compounds are furthermore used in the cleaning of catheters andmedical aids in patients in vivo, or as anticoagulants for thepreservation of blood, plasma and other blood products in vitro. Thecompounds according to the invention are furthermore used for diseasesin which blood coagulation makes a crucial contribution toward thecourse of the disease or represents a source of secondary pathology,such as, for example, in cancer, including metastasis, inflammatorydisorders, including arthritis, and diabetes.

The compounds according to the invention are furthermore used for thetreatment of migraine (F. Morales-Asin et al., Headache, 40, 2000,45-47).

In the treatment of the disorders described, the compounds according tothe invention are also used in combination with other thrombolyticallyactive compounds, such as, for example, with the “tissue plasminogenactivator” t-PA, modified t-PA, streptokinase or urokinase. Thecompounds according to the invention are administered either at the sametime as or before or after the other substances mentioned.

Particular preference is given to simultaneous administration withaspirin in order to prevent recurrence of the clot formation.

The compounds according to the invention are also used in combinationwith blood platelet glycoprotein receptor (IIb/IIIa) antagonists, whichinhibit blood platelet aggregation.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI according to claims 1-20 and pharmaceutically usable derivatives,solvates and stereoisomers thereof, characterised in that

-   a) for the preparation of a compound of the formula I    in which X is CONR² or CONR²C(R³)₂,    a compound of the formula II    in which-   L is Cl, Br, I or a free or reactively functionally modified OH    group,-   and R¹, R¹′, D, M and W are as defined in claim 1,    with the proviso that any further OH and/or amino group present is    protected,    is reacted with a compound of the formula III    Z′-Y-T  III    in which-   Z′ is NHR² or NHR²C(R³)₂,-   and R², Y and T are as defined in claim 1,    and any protecting group is subsequently removed,-   b) and/or in that a radical T, R¹ and/or R¹′ in a compound of the    formula I is converted into another radical T, R¹ and/or R¹′    by, for example,-   i) converting a sulfanyl compound into an imino compound,-   ii) removing an amino-protecting group, and/or    a base or acid of the formula I is converted into one of its salts.

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds. The term solvates of thecompounds is taken to mean adductions of inert solvent molecules ontothe compounds which form owing to their mutual attractive force.Solvates are, for example, mono- or dihydrates or alcoholates.

The term “pharmaceutically usable derivatives” is taken to mean, forexample, the salts of the compounds according to the invention andso-called prodrug compounds.

The term “prodrug derivatives” is taken to mean compounds of the formulaI which have been modified with, for example, alkyl or acyl groups,sugars or oligopeptides and which are rapidly cleaved in the organism toform the active compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The invention also relates to mixtures of the compounds of the formula Iaccording to the invention, for example mixtures of two diastereomers,for example in the ratio 01:01, 01:02, 01:03, 01:04, 01:05, 01:10, 1:100or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

For all radicals which occur more than once, such as, for example, A,their meanings are independent of one another.

Above and below, the radicals and parameters D, M, W, X, Y, T, R¹ andR¹′ are as defined under the formula I, unless expressly statedotherwise.

The following abbreviations are used below:

-   Ac acetyl-   BOC tert-butoxycarbonyl-   CBZ or Z benzyloxycarbonyl-   DCCI dicyclohexylcarbodiimide-   DCM dichloromethane-   DMF dimethylformamide-   EDCI N-ethyl-N,N′-(dimethylaminopropyl)carbodiimide-   EA ethyl acetate-   Et ethyl-   Fmoc 9-fluorenylmethoxycarbonyl-   HOBt 1-hydroxybenzotriazole-   Me methyl-   MBHA 4-methylbenzhydrylamine-   Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl-   HONSu N-hydroxysuccinimide-   OBut tert-butyl ester-   Oct octanoyl-   OMe methyl ester-   OEt ethyl ester-   POA phenoxyacetyl-   TFA trifluoroacetic acid-   Trt trityl(triphenylmethyl).

The ring M is preferably phenyl.

D, if present, may be monosubstituted, disubstituted or trisubstituted,preferably by Hal, A, OR² or N(R²)₂, and/or one CH₂ group in thealkylene chain may also be replaced by a C═O group. Monosubstitution byA or NH₂ is very particularly preferred.

D is preferably —CO—NH—CO, —CO—NH—CH₂—, —NH—CH═CH—, —O—CH═CH—, —N═CH—O—,—N═CH—NH—, —NH—NH—CO—, —NH—N═N—, —NH—CO—CH₂—, —NH—CO—O—, —N═CH—S—,—NH—CO—S—, —NH—CO—NH—, —NH—N═CH—, —S—N═CH—, ═C—S—N═, —O—N═CH—,—O—NH—CO—, —NH—O—CO—, —N═CH—CH═CH—, —CH═N—CH═CH—, —N═N—CH═CH—,—N═CH—N═CH—, —N═CH—CH═N—, —N═N—N═CH—, —NH—CO—CH═CH—, —NH—CH═CH—CO—,—NH—CO—CH₂—CH₂—, —NH—CH₂—CH₂—CO—, —NH—CO—N═CH—, —N═CH—NH—CO—,—NH—CO—NH—CO—, —NH—CO—NH—CH₂—, —CH═N—N═CH—, —N—S⁺═—N—, —O—CH₂—O—,furthermore —CH═N—NH—CO—, —CH═CH—NH—, —O—CH₂CH₂—O—, —CO—NH—NH—CO—,—N═N—NH—CO—, —O—CO—NH—CH₂— or —O—CO—NH—CO—, where, in addition, thealkylene chain and/or a nitrogen present therein may be monosubstituted,disubstituted or trisubstituted by A or NH₂.

In a further embodiment, D is preferably a saturated 3- to 4-memberedalkylene chain, in which from 1 to 3 carbon atoms may be replaced by Nand/or 1 or 2 carbon atoms may be replaced by 1 or 2 O atoms, but whereat most up to 3 carbon atoms are replaced and where, in addition, thealkylene chain and/or or a nitrogen located therein may bemonosubstituted or disubstituted by NH₂, or D is absent.

D is particularly preferably —CH═N—CH═CH—, —CH═CH—N═CH—, NH—N═CH—,—CH═N—NH—, —O—N═CH— or —CH═N—O—, where, in addition, D may bemonosubstituted by NH₂, or D is absent.

A is alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5,6, 7, 8, 9 or 10 carbon atoms. A is preferably methyl, furthermoreethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl,furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl,1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl. A is very particularly preferably alkyl having 1, 2, 3,4, 5 or 6 carbon atoms, preferably methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl,pentafluoroethyl or 1,1,1-trifluoroethyl.

Alkoxy is preferably, for example, methoxy, ethoxy, propoxy, isopropoxy,butoxy, trifluoromethoxy or cyclopentoxy.

Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl.

Alkylene is preferably methylene, ethylene, propylene, butylene,pentylene or hexylene, furthermore branched alkylene.

COR² is for example, CHO or —COA.

—COA (acyl) is preferably acetyl, propionyl, furthermore also butyryl,pentanoyl, hexanoyl or, for example, benzoyl.

Hal is preferably F, Cl or Br, but alternatively I.

R¹ is preferably CN, CONH₂, CONA₂, NH₂, C(═S)NH₂, CH₂NH₂, CH₂CH₂NH₂,—C(═NH)—NH₂ which is unsubstituted or monosubstituted by OH, OCOA orOCOOA, or

where A is preferably alkyl having 1, 2, 3 or 4 carbon atoms.

R¹ is preferably H, —[C(R³)₂]_(n)—N(R³)₂, CON(R²)₂, C(═S)NH₂ or N(R²)₂,particularly preferably H, CH₂NH₂, NH₂, CONH₂ or C(═S)NH₂.

R¹′ is preferably H.

R² is preferably, for example, H or alkyl having 1, 2, 3, 4, 5 or 6carbon atoms.

R²′ is preferably, for example, H or alkyl having 1, 2, 3, 4, 5 or 6carbon atoms.

R²″ is preferably, for example, H or alkyl having 1, 2, 3, 4, 5 or 6carbon atoms.

W is a monocyclic or bicyclic saturated, unsaturated or aromaticcarbocyclic or heterocyclic ring having from 1 to 4 N, O and/or S atoms,which may be monosubstituted or disubstituted by R².

In a preferred embodiment, W is a monocyclic saturated, unsaturated oraromatic carbocyclic or heterocyclic ring having 1 or 2 N, O and/or Satoms, which may be monosubstituted or disubstituted by R².

In a further preferred embodiment, W is, for example, cyclohexanediyl,cyclopentanediyl, phenylene, biphenylene, furandiyl, thiophenediyl,pyrrolediyl, imidazolediyl, pyrazolediyl, oxazolediyl, isoxazolediyl,thiazolediyl, isothiazolediyl, pyridinediyl, pyrimidinediyl,pyrrolidinediyl, piperidinediyl or piperazinediyl, each of which ismonosubstituted or disubstituted by R².

In a further preferred embodiment, W is, for example, cyclohexanediyl,cyclopentanediyl, phenylene, biphenylene, furandiyl, thiophenediyl,pyrrolediyl, imidazolediyl, pyrazolediyl, oxazolediyl, isoxazolediyl,thiazolediyl, isothiazolediyl, pyridinediyl, pyrimidinediyl,pyrrolidinediyl, piperidinediyl or piperazinediyl, each of which isunsubstituted or monosubstituted or disubstituted by A or Hal.

W is particularly preferably pyrazolediyl or thiazolediyl, each of whichis unsubstituted or monosubstituted by A, CONH₂ or COOA, where A is, inparticular, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF₃.

X is preferably CONH, CONHCH₂, CH₂NH or CH₂NHCH₂, very particularlypreferably CONH.

Y is preferably alkylene or Ar-diyl, particularly preferably methylene,ethylene, propylene, or 1,4-phenylene which is unsubstituted ormonosubstituted by A, Cl or F, furthermore also pyridinediyl, preferablypyridine-2,5-diyl.

Y is, in particular, 1,3- or 1,4-phenylene which is unsubstituted ormonosubstituted by methyl, ethyl, propyl, Br, Cl or F, very particularlypreferably 1,4-phenylene.

Ar is preferably phenyl, naphthyl or biphenyl, each of which isunsubstituted or monosubstituted, disubstituted or trisubstituted byHal, A, OH, NH₂, NO₂, CN, COOH, CONH₂, NHCOA, NHCONH₂, NHSO₂A, COH,SO₂NH₂, S(O)_(m)A, —(CH₂)_(n)—COOR²′ or —O—(CH₂)_(o)—COOR²′.

Ar is, for example, unsubstituted phenyl, naphthyl or biphenyl,furthermore preferably phenyl, naphthyl or biphenyl, each of which ismonosubstituted, disubstituted or trisubstituted by A, fluorine,chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy,pentyloxy, hexyloxy, nitro, cyano, formyl, acetyl, propionyl,trifluoromethyl, amino, methylamino, ethylamino, dimethylamino,diethylamino, benzyloxy, sulfonamido, methylsulfonamido,ethylsulfonamido, propylsulfonamido, butylsulfonamido,dimethylsulfonamido, phenylsulfonamido, carboxy, methoxycarbonyl,ethoxycarbonyl or aminocarbonyl.

Het is, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-,4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl,furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-,-3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl,1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-,5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-,4-, 5-, 6-, 7- or 8-quinolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5-or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl,furthermore preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.

The heterocyclic radicals may also be partially or fully hydrogenated.Het can thus also be, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl,2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl,1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-,-3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl,1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl,1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3-or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-quiinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermore preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoro-methylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxo-methylenedioxy)phenyl or alternatively3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

Het¹ has the preferred meanings, such as Het.

T is preferably a monocyclic saturated or unsaturated heterocyclic ringhaving 1 or 2 N and/or O atoms which is monosubstituted or disubstitutedby ═S, ═NR², ═NOR², ═N—CN, ═N—NO₂, ═NCOR², ═NCOOR² or ═NOCOR², inparticular by ═S, ═NR² or ═NOR², and may preferably furthermore bemonosubstituted or disubstituted by A.

T is, in particular, piperidin-1-yl, pyrrolidin-1-yl, 1H-pyridin-1-yl,morpholin-4-yl, piperazin-1-yl, 1,3-oxazolidin-3-yl, 2H-pyridazin-2-yl,azepan-1-yl or 2-azabicyclo[2.2.2]octan-2-yl, pyrazol-2-yl,1,3,4-thiadiazol-3-yl, imidazolidin-1-yl or 1,2-dihydropyrazol-2-yl,each of which is monosubstituted or disubstituted by ═NR², ═S or ═NOR²and may preferably furthermore be monosubstituted or disubstituted by A,CONH₂ or COOA.

T is furthermore particularly preferably, for example,2-iminopiperidin-1-yl, 2-iminopyrrolidin-1-yl, 2-imino-1H-pyridin-1-yl,3-iminomorpholin-4-yl, 4-imino-1H-pyridin-1-yl,2,6-diiminopiperidin-1-yl, 2-iminopiperazin-1-yl,2,6-diiminopiperazin-1-yl, 2,5-diiminopyrrolidin-1-yl,2-imino-1,3-oxazolidin-3-yl, 3-imino-2H-pyridazin-2-yl,2-iminoazepan-1-yl, 2-hydroxy-6-iminopiperazin-1-yl, pyrazol-2-yl,1,2-dihydropyrazol-2-yl, 2-methoxy-6-iminopiperazin-1-yl,2-imino-1,3,4-thiadiazol-3-yl or 2-iminoimidazolidin-1-yl, veryparticularly preferably 2-iminopiperidin-1-yl, and the correspondinghydroxyimino, alkoxyimino, thioxo and ═N—(CH₂)₁₋₃NA′₂ derivatives, whereA′ is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

In a further particularly preferred embodiment, T is, for example,2-iminopyrrolidin-1-yl, 2-iminopiperidin-1-yl,2-imino-1,3,4-thiadiazol-3-yl, 2-iminoimidazolidin-1-yl or3-imino-1,2-dihydropyrazol-2-yl, and the corresponding hydroxyimino,cyanoimino, alkoxyimino and thioxo derivatives, where the heterocyclicradicals may preferably furthermore be monosubstituted or disubstitutedby A, CONH₂ or COOA.

In a further particularly preferred embodiment, T is, for example,2-iminopyrrolidin-1-yl, 2-iminopiperidin-1-yl, 2-thioxopyrrolidin-1-yl,2-imino-1,3,4-thiadiazol-3-yl, 2-methoxyiminopyrrolidin-1-yl,2-hydroxyiminopyrrolidin-1-yl, 2-iminoimidazolidin-1-yl or3-imino-1,2-dihydropyrazol-2-yl, where the heterocyclic radicals maypreferably furthermore be monosubstituted or disubstituted by A, CONH₂or COOA.

The compounds of the formula I may have one or more chiral centres andtherefore occur in various stereoisomeric forms. The formula I coversall these forms.

Accordingly, the invention relates in particular to the compounds of theformula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to Iw, which conformto the formula I and in which the radicals not designated in greaterdetail are as defined under the formula I, but in which

-   -   in Ia D is absent;    -   in Ib M is a phenyl ring;    -   in Ic D is a saturated, fully or partially unsaturated 3- to        4-membered alkylene chain, in which from 1 to 3 carbon atoms may        be replaced by N and/or 1 or 2 carbon atoms may be replaced by 1        or 2 O and/or 1 or 2 S atoms, but where at most up to 3 carbon        atoms are replaced and where, in addition, the alkylene chain        and/or a nitrogen present therein may be monosubstituted,        disubstituted or trisubstituted by Hal, A, OR² or N(R²)₂, and        where, furthermore, one CH₂ group in the alkylene chain may also        be replaced by a C═O group;    -   in Id D is a saturated, fully or partially unsaturated 3- to        4-membered alkylene chain, in which from 1 to 3 carbon atoms may        be replaced by N and/or 1 or 2 carbon atoms may be replaced by 1        or 2 O and/or 1 or 2 S atoms, but where at most up to 3 carbon        atoms are replaced and where, in addition, the alkylene chain        and/or a nitrogen present therein may be monosubstituted,        disubstituted or trisubstituted by A or NH₂;    -   in Ie        -   D is absent or is a saturated 3- to 4-membered alkylene            chain, in which from 1 to 3 carbon atoms may be replaced by            N and/or 1 or 2 carbon atoms may be replaced by 1 or atoms,            but where at most up to 3 carbon atoms are replaced,        -   and where, in addition, the alkylene chain and/or a nitrogen            atom located therein may be monosubstituted or disubstituted            by NH₂;    -   in If        -   D is absent or is —CH═N—CH═CH—, —CH═CH—N═CH—, —NH—N═CH—,            —CH═N—NH—, —O—N═CH— or —CH═N—O—,        -   and where, in addition, D may be monosubstituted by NH₂;    -   in Ig        -   R¹ is H, —[C(R³)₂]_(n)—N(R³)₂, CON(R²)₂, C(═S)NH₂ or N(R²)₂,        -   R¹′ is H;    -   in Ih        -   R¹ is H, CH₂NH₂, CONH₂, C(═S)NH₂ or NH₂,        -   R¹′ is H;    -   in Ii W is a monocyclic saturated, unsaturated or aromatic        carbocyclic or heterocyclic ring having 1 or 2 N, O and/or S        atoms, which may be monosubstituted or disubstituted by R²;    -   in Ij W is cyclohexanediyl, cyclopentanediyl, phenylene,        biphenylene, furandiyl, thiophenediyl, pyrrolediyl,        imidazolediyl, pyrazolediyl, oxazolediyl, isoxazolediyl,        thiazolediyl, isothiazolediyl, pyridinediyl, pyrimidinediyl,        pyrrolidinediyl, piperidinediyl or piperazinediyl, each of which        is unsubstituted or monosubstituted or disubstituted by R²;    -   in Ik W is pyrazolediyl, which is unsubstituted or        monosubstituted by A;    -   in Il X is CONH, CONHCH₂, CH₂NH or CH₂NHCH₂;    -   in Im X is CONH;    -   in In Y is alkylene or Ar-diyl;    -   in Io Y is phenylene which is unsubstituted or monosubstituted        or disubstituted by A, Br, Cl or F;    -   in Ip T is a monocyclic saturated or unsaturated heterocyclic        ring having from 1 to 3 N, O and/or S atoms, which is        monosubstituted or disubstituted by ═S, ═NR², ═NOR², ═N—CN,        ═N—NO₂, ═NCOR², ═NCOOR² or ═NOCOR², and may be monosubstituted        or disubstituted by A, CON(R²)₂ or COOR²;    -   in Iq T is a monocyclic saturated or unsaturated heterocyclic        ring having from 1 to 3 N, O and/or S atoms, which is        monosubstituted or disubstituted by ═S, ═NR², ═N—CN or ═NOR²,        and may be monosubstituted or disubstituted by A, CON(R²)₂ or        COOR²;    -   in Ir T is piperidin-1-yl, pyrrolidin-1-yl, 1H-pyridin-1-yl,        morpholin-4-yl, piperazin-1-yl, 1,3-oxazolidin-3-yl,        2H-pyridazin-2-yl, azepan-1-yl, 2-azabicyclo[2.2.2]octan-2-yl,        pyrazol-2-yl, imidazolidin-1-yl, 1,3,4-thiadiazol-3-yl- or        1,2-dihydropyrazol-2-yl, each of which is monosubstituted or        disubstituted by ═NR², ═S, ═N—CN or ═NOR² and which may        furthermore be monosubstituted or disubstituted by A, CONH₂ or        COOA,    -   in Is T is 2-iminopiperidin-1-yl, 2-iminopyrrolidin-1-yl,        2-imino-1H-pyridin-1-yl, 3-iminomorpholin-4-yl,        4-imino-1H-pyridin-1-yl, 2,6-diiminopiperidin1-yl,        2-iminopiperazin-1-yl, 2,6-diiminopiperazin-1-yl,        2,5-diiminopyrrolidin-1-yl, 2-imino-1,3-oxazolidin-3-yl,        3-imino-2H-pyridazin-2-yl, 2-iminoazepan-1-yl,        2-hydroxy-6-iminopiperazin-1-yl, pyrazol-2-yl,        1,2-dihydropyrazol-2-yl, 2-methoxy-6-iminopiperazin-1-yl,        2-imino-1,3,4-thiadiazol-3-yl, 2-iminoimidazolidin-1-yl, and the        corresponding hydroxyimino, alkoxyimino, thioxo and        ═N—(CH₂)₁₋₃NA′₂ derivatives, where A′ is alkyl having 1, 2, 3,        4, 5 or 6 carbon atoms, and where the heterocyclic rings may        furthermore be monosubstituted or disubstituted by A, CONH₂ or        COOA;    -   in It T is 2-iminopyrrolidin-1-yl, 2-iminopiperidin-1-yl,        2-imino-1,3,4-thiadiazol-3-yl, 2-iminoimidazolidin-1-yl or        3-imino-1,2-dihydropyrazol-2-yl, and the corresponding        hydroxyimino, alkoxyimino and thioxo derivatives, where the        heterocyclic radicals may furthermore be monosubstituted or        disubstituted by A, CONH₂ or COOA;    -   in Iu        -   D is absent or is —CH═N—CH═CH—, —CH═CH—N═CH—, —NH—N═CH—,            —CH═N—NH—, —O—N═CH— or —CH═N—O—,        -   M is a phenyl ring,        -   R¹ is H, CH₂NH₂, CONH₂, C(═S)NH₂ or NH₂,        -   R¹′ is H,        -   W is a monocyclic saturated, unsaturated or aromatic            carbocyclic or heterocyclic ring having 1 or 2 N, O and/or S            atoms, which may be monosubstituted or disubstituted by R²,        -   R² is H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,        -   R²′ is H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,        -   X is CONH, CONHCH₂, CH₂NH or CH₂NHCH₂,        -   Y is alkylene or Ar-diyl,        -   Ar is phenyl, naphthyl or biphenyl, each of which is            unsubstituted or monosubstituted, disubstituted or            trisubstituted by Hal, A, OH, NH₂, NO₂, CN, COOH, CONH₂,            NHCOA, NHCONH₂, NHSO₂A, COH, SO₂NH₂, S(O)_(m)A,            —(CH₂)_(n)—COOR²′ or —O—(CH₂)_(o)—COOR²′,        -   m and n are each, independently of one another, 0, 1 or 2,        -   o is 1, 2 or 3,        -   T is piperidin-1-yl, pyrrolidin-1-yl, 1H-pyridin-1-yl,            morpholin-4-yl, piperazin-1-yl, 1,3-oxazolidin-3-yl,            2H-pyridazin-2-yl, azepan-1-yl,            2-azabicyclo[2.2.2]octan-2-yl, pyrazol-2-yl,            1,3,4-thiadiazol-3-yl, imidazolidin-1-yl or            1,2-dihydropyrazol-2-yl, each of which is monosubstituted or            disubstituted by ═NR², ═N—CN, ═S or ═NOR² and may            furthermore be monosubstituted or disubstituted by A, CONH₂            or COOA;    -   in Iv        -   D is absent or is —CH═N—CH═CH—, —CH═CH—N═CH—, —NH—N═CH—,            —CH═N—NH—, —O—N═CH— or —CH═N—O—,        -   M is a phenyl ring,        -   R¹ is H, CH₂NH₂, CONH₂, C(═S)NH₂ or NH₂,        -   R¹′ is H,        -   W is cyclohexanediyl, cyclopentanediyl, phenylene,            biphenylene, furandiyl, thiophenediyl, pyrrolediyl,            imidazolediyl, pyrazolediyl, oxazolediyl, isoxazolediyl,            thiazolediyl, isothiazolediyl, pyridinediyl, pyrimidinediyl,            pyrrolidinediyl, piperidinediyl or piperazinediyl, each of            which is unsubstituted or monosubstituted or disubstituted            by R²,        -   R² is H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,        -   R²′ is H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,        -   X is CONH, CONHCH₂, CH₂NH or CH₂NHCH₂,        -   Y is phenylene which is unsubstituted or monosubstituted or            disubstituted by A, Br, Cl or F,        -   A is unbranched or branched alkyl having 1, 2, 3, 4, 5 or 6            carbon atoms and/or in addition 1-7H atoms may be replaced            by F,        -   T is piperidin-1-yl, pyrrolidin-1-yl, 1H-pyridin-1-yl,            morpholin-4-yl, piperazin-1-yl, 1,3-oxazolidin-3-yl,            2H-pyridazin-2-yl, azepan-1-yl,            2-azabicyclo[2.2.2]octan-2-yl, pyrazol-2-yl,            1,3,4-thiadiazol-3-yl, imidazolidin-1-yl or            1,2-dihydropyrazol-2-yl, each of which is monosubstituted or            disubstituted by ═NR², ═N—CN, ═S or ═NOR² and may            furthermore be monosubstituted or disubstituted by A, CONH₂            or COOA;    -   in Iw        -   D is absent or is —CH═N—CH═CH—, —CH═CH—N═CH—, —NH—N═CH—,            —CH═N—NH—, —O—N═CH— or —CH═N—O—,        -   M is a phenyl ring,        -   R¹ is H, CH₂NH₂, CONH₂, C(═S)NH₂ or NH₂,        -   R¹′ is H,        -   W is pyrazolediyl or thiazolediyl, each of which is            unsubstituted or monosubstituted by A,        -   X is CONH,        -   Y is phenylene which is unsubstituted or monosubstituted or            disubstituted by A, Br, Cl or F,        -   T is 2-iminopyrrolidin-1-yl, 2-iminopiperidin-1-yl,            2-imino-1,3,4-thiadiazol-3-yl, 2-iminoimidazolidin-1-yl or            3-imino-1,2-dihydropyrazol-2-yl, and the corresponding            hydroxyimino, cyanoimino, alkoxyimino and thioxo            derivatives, where the heterocyclic radicals may furthermore            be monosubstituted or disubstituted by A, CONH₂ or COOA,        -   A is unbranched or branched alkyl having 1, 2, 3, 4, 5 or 6            carbon atoms and/or in addition 1-7H atoms may be replaced            by F;            and pharmaceutically usable derivatives, solvates and            stereoisomers thereof, including mixtures thereof in all            ratios.

Furthermore, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Iaa to Iac, which conformto the formula I and in which the radicals not designated in greaterdetail are as defined under the formula I, but in which

-   -   in Iaa        -   D is absent,        -   M is phenyl,        -   R¹ is —C(═NH)—NH₂ which is unsubstituted or monosubstituted            by OH, or        -   R¹′ is H,        -   W is a monocyclic saturated, unsaturated or aromatic            carbocyclic or heterocyclic ring having 1 or 2 N, O and/or S            atoms, which may be monosubstituted or disubstituted by R²,        -   R² is H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,        -   R²′ is H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,        -   X is CONH, CONHCH₂, CH₂NH or CH₂NHCH₂,        -   Y is alkylene or Ar-diyl,        -   Ar is phenyl, naphthyl or biphenyl, each of which is            unsubstituted or monosubstituted, disubstituted or            trisubstituted by Hal, A, OH, NH₂, NO₂, CN, COOH, CONH₂,            NHCOA, NHCONH₂, NHSO₂A, COH, SO₂NH₂, S(O)_(m)A,            —(CH₂)_(n)—COOR²′ or —O—(CH₂)_(o)—COOR²′,        -   m and n are each, independently of one another, 0, 1 or 2,        -   o is 1, 2 or 3,        -   T is piperidin-1-yl, pyrrolidin-1-yl, 1H-pyridin-1-yl,            morpholin-4-yl, piperazin-1-yl, 1,3-oxazolidin-3-yl,            2H-pyridazin-2-yl, azepan-1-yl,            2-azabicyclo[2.2.2]octan-2-yl, pyrazol-2-yl or            1,2-dihydropyrazol-2-yl, each of which is monosubstituted or            disubstituted by ═NR², ═S or ═NOR² and may furthermore be            monosubstituted or disubstituted by A;    -   in Iab        -   D is absent,        -   M is phenyl,        -   R¹ is —C(═NH)—NH₂ which is unsubstituted or monosubstituted            by OH, or        -   R¹′ is H,        -   W is cyclohexanediyl, cyclopentanediyl, phenylene,            biphenylene, furandiyl, thiophenediyl, pyrrolediyl,            imidazolediyl, pyrazolediyl, oxazolediyl, isoxazolediyl,            thiazolediyl, isothiazolediyl, pyridinediyl, pyrimidinediyl,            pyrrolidinediyl, piperidinediyl or piperazinediyl, each of            which is unsubstituted or monosubstituted or disubstituted            by R²,        -   R² is H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,        -   R²′ is H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,        -   X is CONH, CONHCH₂, CH₂NH or CH₂NHCH₂,        -   Y is phenylene which is unsubstituted or monosubstituted or            disubstituted by A, Br, Cl or F,        -   A is unbranched or branched alkyl having 1, 2, 3, 4, 5 or 6            carbon atoms and/or in addition 1-7H atoms may be replaced            by F,        -   T is piperidin-1-yl, pyrrolidin-1-yl, 1H-pyridin-1-yl,            morpholin-4-yl, piperazin-1-yl, 1,3-oxazolidin-3-yl,            2H-pyridazin-2-yl, azepan-1-yl,            2-azabicyclo[2.2.2]octan-2-yl, pyrazol-2-yl or            1,2-dihydropyrazol-2-yl, each of which is monosubstituted or            disubstituted by ═NR², ═S or ═NOR² and may furthermore be            monosubstituted or disubstituted by A;    -   in Iac        -   D is absent,        -   M is phenyl,        -   R¹ is CN, NH₂, CH₂NH₂, CH₂CH₂NH₂, —C(═NH)—NH₂ which is            unsubstituted or monosubstituted by OH,        -   R¹′ is H,        -   W is pyrazolediyl which is unsubstituted or monosubstituted            by A,        -   X is CONH,        -   Y is phenylene which is unsubstituted or monosubstituted or            disubstituted by A, Br, Cl or F,        -   T is 2-iminopyrrolidin-1-yl, 2-iminopiperidin-1-yl,            2-imino-1,3,4-thiadiazol-3-yl or            3-imino-1,2-dihydropyrazol-2-yl, and the corresponding            hydroxyimino, alkoxyimino and thioxo derivatives, where the            heterocyclic radicals may furthermore be monosubstituted or            disubstituted by A,        -   A is unbranched or branched alkyl having 1, 2, 3, 4, 5 or 6            carbon atoms and/or in addition 1-7H atoms may be replaced            by F;            and pharmaceutically usable derivatives, solvates and            stereoisomers thereof, including mixtures thereof in all            ratios.

The compounds of the formula I and also the starting materials for thepreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants which are known per se, but arenot mentioned here in greater detail.

If desired, the starting materials can also be formed in situ so thatthey are not isolated from the reaction mixture, but instead areimmediately converted further into the compounds of the formula I.

The starting compounds of the formulae II and III are generally known.If they are novel, they can, however, be prepared by methods known perse.

All compounds of the following formula VI (where R=H or methyl; n=3, 4or 5) can be synthesised in accordance with the following scheme:

For example, synthesis of 1-(4-amino-2-methylphenyl)piperidine-2-thione:

Alternative synthesis:

Synthesis of the phenylpiperidinethione unit without a methyl group:

Compounds of the formula I can preferably be obtained by reactingcompounds of the formula II with compounds of the formula III.

The reaction is generally carried out in an inert solvent.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether orethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

In the compounds of the formula II, L is preferably Cl, Br, I or a freeor reactively modified OH group, such as, for example, an activatedester, an imidazolide or alkylsulfonyloxy having 1-6 carbon atoms(preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) orarylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- orp-tolylsulfonyloxy).

Radicals of this type for activation of the carboxyl group in typicalacylation reactions are described inn the literature (for example in thestandard works, such as Houben-Weyl, Methoden der organischen Chemie[Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart).Activated esters are advantageously formed in situ, for example throughaddition of HOBt or N-hydroxysuccinimide.

The reaction is generally carried out in an inert solvent, in thepresence of an acid-binding agent, preferably an organic base, such asDIPEA, triethylamine, dimethylaniline, pyridine, N-methylmorpholin orquinoline, or an excess of the carboxyl component of the formula II.

It may also be favourable to add an alkali or alkaline earth metalhydroxide, carbonate or bicarbonate or another salt of a weak acid ofthe alkali or alkaline earth metals, preferably of potassium, sodium,calcium or caesium.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, and the reaction temperature is between about −30°and 140°, normally between −10° and 90°, in particular between about 0°and about 70°.

Suitable inert solvents are those mentioned above.

Compounds of the formula I can furthermore be obtained by liberatingcompounds of the formula I from one of their functional derivatives bytreatment with a solvolysing or hydrogenolysing agent.

Preferred starting materials for the solvolysis or hydrogenolysis arethose which conform to the formula I, but contain correspondingprotected amino and/or hydroxyl groups instead of one or more free aminoand/or hydroxyl groups, preferably those which carry an amino-protectinggroup instead of an H atom bonded to an N atom, in particular thosewhich carry an R′—N group, in which R′ is an amino-protecting group,instead of an HN group, and/or those which carry an hydroxyl-protectinggroup instead of the H atom of an hydroxyl group, for example thosewhich conform to the formula I, but carry a —COOR″ group, in which R″ isan hydroxyl-protecting group, instead of a —COOH group.

Preferred starting materials are also the oxadiazole derivatives, whichcan be converted into the amidino compounds.

It is also possible for a plurality of—identical or different—protectedamino and/or hydroxyl groups to be present in the molecule of thestarting material. If the protecting groups present are different fromone another, they can in many cases be cleaved off selectively.

The term “amino-protecting group” is known in general terms and relatesto groups which are suitable for protecting (blocking) an amino groupagainst chemical reactions, but which are easy to remove after thedesired chemical reaction has been carried out elsewhere in themolecule. Typical of such groups are, in particular, unsubstituted orsubstituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since theamino-protecting groups are removed after the desired reaction (orreaction sequence), their type and size is furthermore not crucial;however, preference is given to those having 1-20, in particular 1-8,carbon atoms. The term “acyl group” is to be understood in the broadestsense in connection with the present process. It includes acyl groupsderived from aliphatic, araliphatic, aromatic or heterocyclic carboxylicacids or sulfonic acids, and, in particular, alkoxycarbonyl,aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of suchacyl groups are alkanoyl, such as acetyl, propionyl and butyryl;aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl;aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl,ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl)and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ(“carbobenzoxy”), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl,such as Mtr. Preferred amino-protecting groups are BOC and Mtr,furthermore CBZ, Fmoc, benzyl and acetyl.

The term “hydroxyl-protecting group” is likewise known in general termsand relates to groups which are suitable for protecting a hydroxyl groupagainst chemical reactions, but are easily removable after the desiredchemical reaction has been carried out elsewhere in the molecule.Typical of such groups are the above-mentioned unsubstituted orsubstituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.The nature and size of the hydroxyl-protecting groups are not crucialsince they are removed again after the desired chemical reaction orreaction sequence; preference is given to groups having 1-20, inparticular 1-10, carbon atoms. Examples of hydroxyl-protecting groupsare, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl,p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butylare particularly preferred.

The compounds of the formula I are liberated from their functionalderivatives—depending on the protecting group used—for example usingstrong acids, advantageously using TFA or perchloric acid, but alsousing other strong inorganic acids, such as hydrochloric acid orsulfuric acid, strong organic carboxylic acids, such as trichloroaceticacid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid. Thepresence of an additional inert solvent is possible, but is not alwaysnecessary. Suitable inert solvents are preferably organic, for examplecarboxylic acids, such as acetic acid, ethers, such as tetrahydrofuranor dioxane, amides, such as DMF, halogenated hydrocarbons, such asdichloromethane, furthermore also alcohols, such as methanol, ethanol orisopropanol, and water. Mixtures of the above-mentioned solvents arefurthermore suitable. TFA is preferably used in excess without additionof a further solvent, and perchloric acid is preferably used in the formof a mixture of acetic acid and 70% perchloric acid in the ratio 9:1.The reaction temperatures for the cleavage are advantageously betweenabout 0 and about 50°, preferably between 15 and 30° (room temperature).

The BOC, OBut and Mtr groups can, for example, preferably be cleaved offusing TFA in dichloromethane or using approximately 3 to 5N HCl indioxane at 15-30°, and the FMOC group can be cleaved off using anapproximately 5 to 50% solution of dimethylamine, diethylamine orpiperidine in DMF at 15-30°.

Protecting groups which can be removed hydrogenolytically (for exampleCBZ, benzyl or the liberation of the amidino group from its oxadiazolederivative) can be cleaved off, for example, by treatment with hydrogenin the presence of a catalyst (for example a noble-metal catalyst, suchas palladium, advantageously on a support, such as carbon). Suitablesolvents here are those indicated above, in particular, for example,alcohols, such as methanol or ethanol, or amides, such as DMF. Thehydrogenolysis is generally carried out at temperatures between about 0and 100° and pressures between about 1 and 200 bar, preferably at 20-30°and 1-10 bar. Hydrogenolysis of the CBZ group succeeds well, forexample, on 5 to 10% Pd/C in methanol or using ammonium formate (insteadof hydrogen) on Pd/C in methanol/DMF at 20-30°.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane,trifluoromethylbenzene, chloroform or dichloromethane; alcohols, such asmethanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF)or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones,such as acetone or butanone; amides, such as acetamide,dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF);nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide(DMSO); carbon disulfide; carboxylic acids, such as formic acid oracetic acid; nitro compounds, such as nitromethane or nitrobenzene;esters, such as ethyl acetate, or mixtures of the said solvents.

Esters can be saponified, for example, using acetic acid or using NaOHor KOH in water, water/THF or water/dioxane, at temperatures between 0and 100°.

Free amino groups can furthermore be acylated in a conventional mannerusing an acid chloride or anhydride or alkylated using an unsubstitutedor substituted alkyl halide or reacted with CH₃—C(═NH)—OEt,advantageously in an inert solvent, such as dichloromethane or THFand/or in the presence of a base, such as triethylamine or pyridine, attemperatures between −60 and +30°.

A base of the formula I can be converted into the associatedacid-addition salt using an acid, for example by reaction of equivalentamounts of the base and the acid in an inert solvent, such as ethanol,followed by evaporation. Suitable acids for this reaction are, inparticular, those which give physiologically acceptable salts. Thus, itis possible to use inorganic acids, for example sulfuric acid, nitricacid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid,phosphoric acids, such as orthophosphoric acid, or sulfamic acid,furthermore organic acids, in particular aliphatic, alicyclic,araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic,sulfonic or sulfuric acids, for example formic acid, acetic acid,propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinicacid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaricacid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinicacid, isonicotinic acid, methane- or ethanesulfonic acid,ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids,and laurylsulfuric acid. Salts with physiologically unacceptable acids,for example picrates, can be used for the isolation and/or purificationof the compounds of the formula I.

On the other hand, compounds of the formula I can be converted into thecorresponding metal salts, in particular alkali metal or alkaline earthmetal salts, or into the corresponding ammonium salts using bases (forexample sodium hydroxide, potassium hydroxide, sodium carbonate orpotassium carbonate). It is also possible to use physiologicallyacceptable organic bases, such as, for example, ethanolamine.

Compounds of the formula I according to the invention may be chiralowing to their molecular structure and may accordingly occur in variousenantiomeric forms. They can therefore exist in racemic or in opticallyactive form.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theintermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the R andS forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitable N-protected amino acids(for example N-benzoylproline) or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantage ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Examplesof suitable eluents for this purpose are aqueous or alcoholic solventmixtures, such as, for example, hexane/isopropanol/acetonitrile, forexample in the ratio 82:15:3.

The invention furthermore relates to the use of compounds of the formulaI and/or their physiologically acceptable salts for the preparation of amedicament (pharmaceutical preparation), in particular by non-chemicalmethods. They can be converted here into a suitable dosage form togetherwith at least one solid, liquid and/or semiliquid excipient or assistantand, if desired, in combination with one or more further activeingredients.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or its pharmaceutically usablederivatives, solvates and stereoisomers, including mixtures thereof inall ratios, and optionally excipients and/or assistants.

These preparations can be used as medicaments in human or veterinarymedicine. Suitable excipients are organic or inorganic substances whichare suitable for enteral (for example oral), parenteral or topicaladministration and do not react with the novel compounds, for examplewater, vegetable oils, benzyl alcohols, alkylene glycols, polyethyleneglycols, glycerol triacetate, gelatin, carbohydrates, such as lactose orstarch, magnesium stearate, talc or vaseline. Suitable for oraladministration are, in particular, tablets, pills, coated tablets,capsules, powders, granules, syrups, juices or drops, suitable forrectal administration are suppositories, suitable for parenteraladministration are solutions, preferably oil-based or aqueous solutions,furthermore suspensions, emulsions or implants, and suitable for topicalapplication are ointments, creams or powders or also as nasal sprays.The novel compounds may also be lyophilised and the resultantlyophilisates used, for example, to prepare injection preparations. Thepreparations indicated may be sterilised and/or comprise assistants,such as lubricants, preservatives, stabilisers and/or wetting agents,emulsifying agents, salts for modifying the osmotic pressure, buffersubstances, colorants and flavours and/or a plurality of further activeingredients, for example one or more vitamins.

The compounds of the formula I and their physiologically acceptablesalts can be used for combating thromboembolic diseases, such asthrombosis, myocardial infarction, arteriosclerosis, inflammation,apoplexia, angina pectoris, restenosis after angioplasty, claudicatiointermittens, tumours, tumour diseases and/or tumour metastases.

In general, the substances according to the invention are preferablyadministered in doses between about 1 and 500 mg, in particular between5 and 100 mg, per dosage unit. The daily dose is preferably betweenabout 0.02 and 10 mg/kg of body weight. However, the specific dose foreach patient depends on a wide variety of factors, for example on theefficacy of the specific compound employed, on the age, body weight,general state of health, sex, on the diet, on the time and method ofadministration, on the excretion rate, medicament combination andseverity of the particular disease to which the therapy applies. Oraladministration is preferred.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or its pharmaceutically usablederivatives, solvates and stereoisomers, including mixtures thereof inall ratios, and at least one further medicament active ingredient.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula I and/or its    pharmaceutically usable derivatives, solvates and stereoisomers,    including mixtures thereof in all ratios, and-   an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules each containing an effective amount of a compound of theformula I and/or its pharmaceutically usable derivatives, solvates andstereoisomers, including mixtures thereof in all ratios,

-   and an effective amount of a further medicament active ingredient in    dissolved or lyophilised form.

The invention furthermore relates to the use of compounds of the formulaI and/or their pharmaceutically usable derivatives, solvates andstereoisomers, including mixtures thereof in all ratios,

-   for the preparation of a medicament for the treatment of thromboses,    myocardial infarction, arteriosclerosis, inflammation, apoplexia,    angina pectoris, restenosis after angioplasty, claudicatio    intermittens, migraine, tumours, tumour diseases and/or tumour    metastases,-   in combination with at least one further medicament active    ingredient.

Above and below, all temperatures are given in ° C. In the followingexamples, ‘conventional work-up’ means that water is added if necessary,the pH is adjusted, if necessary, to between 2 and 10, depending on theconstitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate and evaporated, and the product is purifiedby chromatography on silica gel and/or by crystallisation. Rf values onsilica gel; eluent: ethyl acetate/methanol 9:1. Mass spectrometry (MS):EI (electron impact ionisation) M⁺ FAB (fast atom bombardment) (M + H)⁺ESI (electrospray ionisation) (M + H)⁺ (unless stated otherwise)

EXAMPLE 1

Preparation of an Amine Unit:

10 g (48.95 mmol) of 1-(4-amino-2-methylphenyl)piperidin-2-one areheated to the boil in 70 ml of anhydrous toluene together with 9.9 g(24.48 mmol) of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane2,4-disulfide (Lawesson's reagent). After 40 minutes, the solvent isremoved, and the residue is taken up in dichloromethane (DCM)/1 Maqueous hydrochloric acid. After repeated washing with DCM, a pH of 12is set using conc. sodium hydroxide solution. Extraction with DCM,drying over Na₂SO₄ and evaporation of the solvent give 9.25 g (41.98mmol) of 1-(4-amino-2-methylphenyl)piperidine-2-thione.

EXAMPLE 2

Preparation of an Amine Unit:

2.1 15 g (78.8 mmol) of 1-(4-aminophenyl)piperidin-2-one are heated tothe boil together with 16.0 g (39.5 mmol) of2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide(Lawesson's reagent) in 100 ml of anhydrous toluene. After 45 minutes,the solvent is evaporated, and the residue is taken up indichloromethane and 2 N HCl. The aqueous phase is extracted three timeswith dichloromethane and adjusted to a pH of 12 using conc. NaOH.Extraction with dichloromethane, drying over sodium sulfate andevaporation of the solvent give 1-(4-aminophenyl)piperidine-2-thione asa colourless solid, ESI 207.

2.2 1.25 ml (20.0 mmol) of iodomethane are added to a solution of 3.74 g(18.1 mmol) of 1-(4-aminophenyl)piperidine-2-thione in 30 ml of acetone,and the mixture is stirred at room temperature for 48 hours. Thereaction mixture is evaporated, giving1-(4-aminophenyl)-6-methylsulfanyl-2,3,4,5-tetrahydropyridinium iodideas a brownish solid; ESI 221.

2.3 3.5 ml (25 mmol) of triethylamine are added to a solution of 2.68 g(12.1 mmol) of1-(4-aminophenyl)-6-methylsulfanyl-2,3,4,5-tetrahydropyridinium iodideand 1.01 g (12.1 mmol) of O-methylhydroxylammonium chloride in 30 ml ofethanol, and the mixture is stirred at room temperature for 20 hours.The reaction mixture is evaporated and taken up in water, and theresultant precipitate is filtered off, giving1-(4-aminophenyl)-piperidin-2-one O-methyl oxime as a colourless solid;ESI 220.

EXAMPLE 3 Preparation ofN-[4-(2-iminopyrrolidin-1-yl)phenyl]-2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide(“AA”)

3.1 430 mg (1.53 mmol) of2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid arehydrogenated on Raney nickel in 10 ml of 10% ammonia in methanol.Work-up and precipitation using ether give 370 mg of2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid.

3.2 370 mg (1.3 mmol) of2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acidare suspended in 6 ml of water, and 303 mg (2.86 mmol) of sodiumcarbonate are added. A solution of 312 mg (1.43 mmol) of di-tert-butyldicarbonate in 12 ml of 1,4-dioxane is subsequently added dropwise tothe reaction mixture, and the mixture is stirred at room temperature for18 hours. Conventional work-up gives 360 mg of2-[3-(tert-butoxycarbonylaminomethyl)phenyl]-5-trifluoromethyl-2H-pyrazole-3-carboxylicacid as product.

3.3 360 mg (0.93 mmol) of2-[3-(tert-butoxycarbonylaminomethyl)-phenyl]-5-trifluoromethyl-2H-pyrazole-3-carboxylicacid in 2.5 ml of N,N-dimethylformamide are reacted with 211 mg (1.0mmol) of 4-(2-iminopyrrolidin-1-yl)phenylamine hydrochloride withaddition of 192 mg (1 mmol) ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 153 mg(1.0 mmol) of 1-hydroxybenzotriazole hydrate. Work-up gives 333 mg oftert-butyl(3-{5-[4-(2-iminopyrrolidin-1-yl)phenylcarbamoyl]-3-trifluoromethylpyrazol-1-yl}benzyl)carbamate.

3.4 333 mg (0.61 mmol) oftert-butyl(3-{5-[4-(2-iminopyrrolidin-1-yl)phenylcarbamoyl]-3-trifluoromethylpyrazol-1-yl}benzyl)carbamateare dissolved in 1 ml of ethanol, and 5 ml of HCl in ether are added.Evaporation and precipitation using ether give 289 mg ofN-[4-(2-iminopyrrolidin-1-yl)phenyl]-2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide(“AA”) in the form of the dihydrochloride as product.

EXAMPLE 4

4.1 Analogously to Example 3, reaction of

-   2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic    acid with-   1-(4-aminophenyl)pyrrolidine-2-thione gives the compound-   N-[4-(2-thioxopyrrolidin-1-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide.

4.2 Analogously to Example 3, reaction of

-   2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic    acid with-   1-(4-amino-2-chlorophenyl)pyrrolidine-2-thione gives the compound-   N-[3-chloro-4-(2-thioxopyrrolidin-1-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide    (“BB”), ESI 508.

4.3 Analogously to Example 3, reaction of

-   2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic    acid with-   1-(4-aminophenyl)-2-iminopyrrolidine gives the compound-   N-[4-(2-iminopyrrolidin-1-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,    ESI 457.

EXAMPLE 5

Analogously to Example 3, reaction of

-   2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic    acid with-   1-(4-aminophenyl)pyrrolidin-2-one O-methyl oxime,-   1-(4-amino-2-methylphenyl)pyrrolidin-2-one O-methyl oxime,-   gives the compounds-   N-[4-(2-methoxyiminopyrrolidin-1-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,    ESI 487;-   N-[3-methyl-4-(2-methoxyiminopyrrolidin-1-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,    ESI 515.

EXAMPLE 6

6.1 Analogously to Example 3, reaction of

-   2-(3-BOC-aminobenzo[d]isoxazol-5-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic    acid with-   4-(2-iminopyrrolidin-1-yl)phenylamine,-   4-(2-imino-5-methyl-3H-1,3,4-thiadiazol-3-yl)phenylamine,-   3-bromo-4-(2-imino-5-methyl-3H-1,3,4-thiadiazol-3-yl)phenylamine,-   4-(1,5-dimethyl-3-imino-1,2-dihydropyrazol-2-yl)phenylamine,    and subsequent removal of BOC gives the compounds-   N-[4-(2-iminopyrrolidin-1-yl)phenyl]-2-(3-aminobenzo[d]isoxazol-5-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,-   N-[4-(2-imino-5-methyl-3H-1,3,4-thiadiazol-3-yl)phenyl]-2-(3-aminobenzo[d]isoxazol-5-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,-   N-[3-bromo-4-(2-imino-5-methyl-3H-1,3,4-thiadiazol-3-yl)phenyl]-2-(3-aminobenzo[d]isoxazol-5-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,-   N-[4-(1,5-dimethyl-3-imino-1,2-dihydropyrazol-2-yl)phenyl]-2-(3-aminobenzo[d]isoxazol-5-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide.

6.2 Analogously to Example 3, reaction of

-   2-(3-BOC-aminobenzo[d]isoxazol-5-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic    acid with-   1-(4-aminophenyl)pyrrolidine-2-thione and subsequent removal of BOC    gives the compound-   N-[4-(2-thioxopyrrolidin-1-yl)phenyl]-2-(3-aminobenzo[d]isoxazol-5-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide.

6.3 Analogously to Example 3, reaction of

-   2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic    acid with-   3-bromo-4-(2-imino-5-methyl-3H-1,3,4-thiadiazol-3-yl)phenylamine,-   4-(2-imino-5-methyl-3H-1,3,4-thiadiazol-3-yl)phenylamine,-   4-(2-iminoimidazolidin-1-yl)phenylamine,-   4-(2-iminoimidazolidin-1-yl)-3-methylphenylamine,-   4-(2-cyanoiminoimidazolidin-1-yl)phenylamine,-   4-(2-cyanoimino-3-methylimidazolidin-1-yl)phenylamine,-   4-(2-imino-5-ethyl-3H-1,3,4-thiadiazol-3-yl)phenylamine,-   4-(2-imino-5-aminocarbonyl-3H-1,3,4-thiadiazol-3-yl)phenylamine,-   4-(2-imino-5-ethoxycarbonyl-3H-1,3,4-thiadiazol-3-yl)phenylamine,    gives the compounds-   N-[3-bromo-4-(2-imino-5-methyl-3H-1,3,4-thiadiazol-3-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,    ESI 567, 568;-   N-[4-(2-imino-5-methyl-3H-1,3,4-thiadiazol-3-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,    ESI 488;-   N-[4-(2-iminoimidazolidin-1-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide;-   N-[4-(2-iminoimidazolidin-1-yl)-3-methylphenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide;-   N-[4-(2-cyanoiminoimidazolidin-1-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide    (“CA”);-   N-[4-(2-cyanoimino-3-methylimidazolidin-1-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide;-   N-[4-(2-imino-5-ethyl-3H-1,3,4-thiadiazol-3-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide    (“CB”),-   N-[4-(2-imino-5-aminocarbonyl-3H-1,3,4-thiadiazol-3-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,-   N-[4-(2-imino-5-ethoxycarbonyl-3H-1,3,4-thiadiazol-3-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide.

6.4 Analogously to Example 3, reaction of

-   5-(3-aminocarbonylphenyl)-2-methylthiazole-4-carboxylic acid with-   4-(2-imino-5-ethyl-3H-1,3,4-thiadiazol-3-yl)phenylamine    gives the compound-   N-[4-(2-imino-5-ethyl-3H-1,3,4-thiadiazol-3-yl)phenyl]-5-(3-aminocarbonylphenyl)-2-methylthiazole-4-carboxamide.

6.5 Analogously to Example 3, reaction of

-   2-(3-aminocarbonylphenyl)-5-methyl-2H-pyrazole-3-carboxylic acid    with 4-(2-imino-5-ethyl-3H-1,3,4-thiadiazol-3-yl)phenylamine    gives the compound-   N-[4-(2-imino-5-ethyl-3H-1,3,4-thiadiazol-3-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-methyl-2H-pyrazole-3-carboxamide.

EXAMPLE 7

7.1 Analogously to Example 3, reaction of

-   2-(3-BOC-amino-1H-indazol-5-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic    acid with-   1-(4-aminophenyl)pyrrolidin-2-one O-methyl oxime,-   1-(4-aminophenyl)pyrrolidine-2-thione    and subsequent removal of BOC gives the compounds-   N-[4-(2-methoxyiminopyrrolidin-1-yl)phenyl]-2-(3-amino-1H-indazol-5-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,-   N-[4-(2-thioxopyrrolidin-1-yl)phenyl]-2-(3-amino-1H-indazol-5-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide.

EXAMPLE 8

Analogously to Example 3, reaction of

-   2-(3-thiocarbamoylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic    acid with-   1-(4-aminophenyl)pyrrolidin-2-one O-methyl oxime gives the compound-   N-[4-(2-methoxyiminopyrrolidin-1-yl)phenyl]-2-(3-thiocarbamoylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide.

EXAMPLE 9 Preparation ofN-[4-(2-hydroxyiminopyrrolidin-1-yl)phenyl]-2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide

Hydroxylammonium hydrochloride and triethylamine are added to a solutionofN-[4-(2-methylsulfanylpyrrolidin-1-yl)phenyl]-2-(3-BOC-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,iodide in ketone-free ethanol, and the mixture is stirred at roomtemperature.

After 20 hours, the mixture is evaporated to dryness, and the residue isstirred into water and filtered off. The crude product is dried, and 20ml of HCl in ether are added. After 20 hours, the solvent is removedunder reduced pressure, and the product is dried by stirring with ether,givingN-[4-(2-hydroxyiminopyrrolidin-1-yl)phenyl]-2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide.

Pharmacological Data

Affinity to Receptors TABLE 1 Compound TF/FVIIa-IC₅₀ No. FXa-IC₅₀ [M][M] “AA” 9.6 × 10⁻⁹ 2.3 × 10⁻⁸ “BB” 3.3 × 10⁻⁷ 1.8 × 10⁻⁷ “CA” 2.0 ×10⁻⁷ 6.9 × 10⁻⁸ “CB” 9.2 × 10⁻⁸ 1.5 × 10⁻⁷

The following examples relate to pharmaceutical preparations:

EXAMPLE A Injection Vials

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

EXAMPLE B Suppositories

A mixture of 20 g of an active ingredient of the formula I with 100 g ofsoya lecithin and 1400 g of cocoa butter is melted, poured into mouldsand allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed to give tablets in a conventional manner in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F Coated Tablets

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1. Compounds of the formula I

in which D is absent or is a saturated, fully or partially unsaturated3- to 4-membered alkylene chain, in which from 1 to 3 carbon atoms maybe replaced by N and/or 1 or 2 carbon atoms may be replaced by 1 or 2 Oand/or 1 or 2 S atoms, but where at most up to 3 carbon atoms arereplaced and where, in addition, the alkylene chain and/or a nitrogenpresent therein may be monosubstituted, disubstituted or trisubstitutedby Hal, A, —[C(R³)₂]_(n)-Ar, —[C(R³)₂]_(n)-Het,—[C(R³)₂]_(n)-cycloalkyl, OR², N(R²)₂, NO₂, CN, COOR², CON(R²)₂, NR²COA,NR²SO₂A, COR², SO₂NR² and/or S(O)_(m)A, and where, furthermore, one CH₂group in the alkylene chain may also be replaced by a C═O group, M is aphenyl ring or an aromatic heterocyclic ring, which may contain 1-2 N, Oand/or S atoms, R¹ and R¹′ are each, independently of one another, H,Hal, A, OR², N(R²)₂, NO₂, CN, COOR², CON(R²)₂, C(═S)N(R²)₂,—[C(R³)₂]_(n)-Ar, —[C(R³)₂]_(n)-Het, —[C(R³)₂]_(n)-cycloalkyl,—[C(R³)₂]_(n)—N(R³)₂, CN, —C(═NH)—NH₂ which is unsubstituted ormonosubstituted by C(═O)R³, COOR³, OR³, OCOR³, OCOOR³ or by aconventional amino-protecting group, or

R² is H, A, —[C(R³)₂]_(n)-Ar, —[C(R³)₂]_(n)-Het,—[C(R³)₂]_(n)-cycloalkyl, —[C(R³)₂]_(n)—N(R³)₂ or —[C(R³)₂]_(n)—OR³, R²′is H, A, —[C(R³)₂]_(n)-Ar′, —[C(R³)₂]_(n)-Het′,—[C(R³)₂]_(n)-cycloalkyl, —[C(R³)₂]_(n)—N(R³)₂ or —[C(R³)₂]_(n)—OR³, R²″is H, A, —[C(R³)₂]_(n)-cycloalkyl, —[C(R³)₂]_(n)—N(R³)₂ or—[C(R³)₂]_(n)—OR³, R³ is H or A, W is a monocyclic or bicyclicsaturated, unsaturated or aromatic carbocyclic or heterocyclic ringhaving from 1 to 4 N, O and/or S atoms, which may be monosubstituted ordisubstituted by R², X is CONR², CONR²C(R³)₂, —C(R³)₂NR²,—C(R³)₂NR²C(R³)₂, —C(R³)₂O—, —C(R³)₂OC(R³)₂— or NR²CO, Y is alkylene,cycloalkylene, Het-diyl or Ar-diyl, T is a monocyclic or bicyclic,saturated, unsaturated or aromatic carbocyclic or heterocyclic ringhaving from 1 to 4 N, O and/or S atoms which is monosubstituted ordisubstituted by ═S, ═NR², ═N—CN, ═N—NO₂, ═NOR², ═NCOR², ═NCOOR² or═NOCOR² and may furthermore be monosubstituted, disubstituted ortrisubstituted by Hal, A, —[C(R³)₂]_(n)—Ar, —[C(R³)₂]_(n)-Het,—[C(R³)₂]_(n)-cycloalkyl, OR³, N(R³)₂, NO₂, CN, COOR², CON(R²)₂, NR²COA,NR²CON(R²)₂, NR²SO₂A, COR², SO₂NR² and/or S(O)_(m)A, A is unbranched orbranched alkyl having 1-10 carbon atoms, in which one or two CH₂ groupsmay be replaced by O or S atoms and/or by —CH═CH— groups, and/or inaddition 1-7H atoms may be replaced by F, Ar is phenyl, naphthyl orbiphenyl, each of which is unsubstituted or monosubstituted,disubstituted or trisubstituted by Hal, A, OR³, N(R³)₂, NO₂, CN, COOR³,CON(R³)₂, NR³COA, NR³CON(R³)₂, NR³SO₂A, COR³, SO₂N(R³)₂, S(O)_(m)A,—[C(R³)₂]_(n)—COOR²′ or —O—[C(R³)₂]_(o)—COOR²′, Ar′ is phenyl or benzyl,each of which is unsubstituted or monosubstituted or disubstituted byHal, Het is a monocyclic or bicyclic, saturated, unsaturated or aromaticheterocyclic ring having from 1 to 4 N, O and/or S atoms, which may beunsubstituted or monosubstituted, disubstituted or trisubstituted bycarbonyl oxygen, ═S, ═N(R³)₂, Hal, A, —[C(R³)₂]_(n)-Ar,—[C(R³)₂]_(n)-Het¹, —[C(R³)₂]_(n)-cycloalkyl, —[C(R³)₂]_(n)—OR²′,—[C(R³)₂]_(n)—N(R²′)₂, NO₂, CN, —[C(R³)₂]_(n)—COOR²′,—[C(R³)₂]_(n)—CON(R²′)₂, —[C(R³)₂]_(n)—NR²′COA, NR²′CON(R²′)₂,—[C(R³)₂]_(n)—NR²′SO₂A, COR²′, SO₂NR²′ and/or S(O)_(m)A, Het¹ is amonocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclicring having 1 or 2 N, O and/or S atoms, which may be unsubstituted ormonosubstituted or disubstituted by carbonyl oxygen, ═S, ═N(R³)₂, Hal,A, OR²″, N(R²″)₂, NO₂, CN, COOR²″, CON(R²″)₂, NR²″COA, NR²″CON(R²″)₂,NR²″SO₂A, COR²″, SO₂NR²″ and/or S(O)_(m)A, Hal is F, Cl, Br or I, n is0, 1 or 2, m is 0, 1 or 2, o is 1, 2 or 3, and pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios.
 2. Compounds of the formula I according to claim1, in which D is absent, and pharmaceutically usable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios.
 3. Compounds of the formula I according to claim 1, in which Mis a phenyl ring, and pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 4.Compounds of the formula I according to claim 1, in which D is asaturated, fully or partially unsaturated 3- to 4-membered alkylenechain, in which from 1 to 3 carbon atoms may be replaced by N and/or 1or 2 carbon atoms may be replaced by 1 or 2 O and/or 1 or 2 S atoms, butwhere at most up to 3 carbon atoms are replaced and where, in addition,the alkylene chain and/or a nitrogen present therein may bemonosubstituted, disubstituted or trisubstituted by Hal, A, OR² orN(R²)₂, and where, furthermore, one CH₂ group in the alkylene chain mayalso be replaced by a C═O group, and pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios.
 5. Compounds of the formula I according to claim1, in which D is a saturated, fully or partially unsaturated 3- to4-membered alkylene chain, in which from 1 to 3 carbon atoms may bereplaced by N and/or 1 or 2 carbon atoms may be replaced by 1 or 2 Oand/or 1 or 2 S atoms, but where at most up to 3 carbon atoms arereplaced and where, in addition, the alkylene chain and/or a nitrogenpresent therein may be monosubstituted, disubstituted or trisubstitutedby A or NH₂, and pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 6.Compounds of the formula I according to claim 1, in which D is absent oris a saturated 3- to 4-membered alkylene chain, in which from 1 to 3carbon atoms may be replaced by N and/or 1 or 2 carbon atoms may bereplaced by 1 or 2 O atoms, but where at most up to 3 carbon atoms arereplaced, and where, in addition, the alkylene chain and/or a nitrogenatom located therein may be monosubstituted or disubstituted by NH₂, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios.
 7. Compounds of the formula Iaccording to claim 1, in which D is absent or is —CH═N—CH═CH—,—CH═CH—N═CH—, —NH—N═CH—, —CH═N—NH—, —O—N═CH— or —CH═N—O—, and where, inaddition, D may be monosubstituted by NH₂, and pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios.
 8. Compounds of the formula I according to claim1, in which R¹ is H, —[C(R³)₂]_(n)—N(R³)₂, CON(R²)₂, C(═S)NH₂ or N(R²)₂,R¹′ is H, and pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 9.Compounds of the formula I according to claim 1, in which R¹ is H,CH₂NH₂, CONH₂, C(═S)NH₂ or NH₂, R¹′ is H, and pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios.
 10. Compounds of the formula I according to claim1, in which W is a monocyclic saturated, unsaturated or aromaticcarbocyclic or heterocyclic ring having 1 or 2 N, O and/or S atoms,which may be monosubstituted or disubstituted by R², andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios.
 11. Compounds of the formula Iaccording to claim 1, in which W is cyclohexanediyl, cyclopentanediyl,phenylene, biphenylene, furandiyl, thiophenediyl, pyrrolediyl,imidazolediyl, pyrazolediyl, oxazolediyl, isoxazolediyl, thiazolediyl,isothiazolediyl, pyridinediyl, pyrimidinediyl, pyrrolidinediyl,piperidinediyl or piperazinediyl, each of which is unsubstituted ormonosubstituted or disubstituted by R², and pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios.
 12. Compounds of the formula I according to claim1, in which W is pyrazolediyl, which is unsubstituted or monosubstitutedby A, and pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 13.Compounds of the formula I according to claim 1, in which X is CONH,CONHCH₂, CH₂NH or CH₂NHCH₂, and pharmaceutically usable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios.
 14. Compounds of the formula I according to claim 1, in which Xis CONH, and pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 15.Compounds of the formula I according to claim 1, in which Y is alkyleneor Ar-diyl, and pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 16.Compounds of the formula I according to claim 1, in which Y is phenylenewhich is unsubstituted or monosubstituted or disubstituted by A, Br, Clor F, and pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 17.Compounds of the formula I according to claim 1, in which T is amonocyclic saturated or unsaturated heterocyclic ring having from 1 to 3N, O and/or S atoms, which is monosubstituted or disubstituted by ═S,═NR², ═NOR², ═N—CN, ═N—NO₂, ═NCOR², ═NCOOR² or ═NOCOR², and may bemonosubstituted or disubstituted by A, CON(R²)₂ or COOR², andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios.
 18. Compounds of the formula Iaccording to claim 1, in which T is a monocyclic saturated orunsaturated heterocyclic ring having from 1 to 3 N, O and/or S atoms,which is monosubstituted or disubstituted by ═S, ═NR², ═N—CN or ═NOR²,and may be monosubstituted or disubstituted by A, CON(R²)₂ or COOR², andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios.
 19. Compounds of the formula Iaccording to claim 1, in which T is piperidin-1-yl, pyrrolidin-1-yl,1H-pyridin-1-yl, morpholin-4-yl, piperazin-1-yl, 1,3-oxazolidin-3-yl,2H-pyridazin-2-yl, azepan-1-yl, 2-azabicyclo[2.2.2]octan-2-yl,pyrazol-2-yl, imidazolidin-1-yl, 1,3,4-thiadiazol-3-yl or1,2-dihydropyrazol-2-yl, each of which is monosubstituted ordisubstituted by ═NR², ═S, ═N—CN or ═NOR² and may furthermore bemonosubstituted or disubstituted by A, CONH₂ or COOA, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios.
 20. Compounds of the formula Iaccording to claim 1, in which T is 2-iminopiperidin-1-yl,2-iminopyrrolidin-1-yl, 2-imino-1H-pyridin-1-yl, 3-iminomorpholin-4-yl,4-imino-1H-pyridin-1-yl, 2,6-diiminopiperidin-1-yl,2-iminopiperazin-1-yl, 2,6-diiminopiperazin-1-yl,2,5-diiminopyrrolidin-1-yl, 2-imino-1,3-oxazolidin-3-yl,3-imino-2H-pyridazin-2-yl, 2-iminoazepan-1-yl,2-hydroxy-6-iminopiperazin-1-yl, pyrazol-2-yl, 1,2-dihydropyrazol-2-yl,2-methoxy-6-iminopiperazin-1-yl, 2-imino-1,3,4-thiadiazol-3-yl,2-iminoimidazolidin-1-yl, and the corresponding hydroxyimino,alkoxyimino, thioxo and ═N—(CH₂)₁₋₃NA′₂ derivatives, where A′ is alkylhaving 1, 2, 3, 4, 5 or 6 carbon atoms, and where the heterocyclic ringsmay furthermore be monosubstituted or disubstituted by A, CONH₂ or COOA,and pharmaceutically usable derivatives, solvates and stereoisomersthereof, including mixtures thereof in all ratios.
 21. Compounds of theformula I according to claim 1, in which T is 2-iminopyrrolidin-1-yl,2-iminopiperidin-1-yl, 2-imino-1,3,4-thiadiazol-3-yl,2-iminoimidazolidin-1-yl or 3-imino-1,2-dihydropyrazol-2-yl, and thecorresponding hydroxyimino, alkoxyimino and thioxo derivatives, wherethe heterocyclic radicals may furthermore be monosubstituted ordisubstituted by A, CONH₂ or COOA, and pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios.
 22. Compounds of the formula I according to claim1, in which D is absent or is —CH═N—CH═CH—, —CH═CH—N═CH—, —NH—N═CH—,—CH═N—NH—, —O—N═CH— or —CH═N—O—, M is a phenyl ring, R¹ is H, CH₂NH₂,CONH₂, C(═S)NH₂ or NH₂, R¹′ is H, W is a monocyclic saturated,unsaturated or aromatic carbocyclic or heterocyclic ring having 1 or 2N, O and/or S atoms, which may be monosubstituted or disubstituted byR², R² is H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, R²′ is H oralkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, X is CONH, CONHCH₂, CH₂NHor CH₂NHCH₂, Y is alkylene or Ar-diyl, Ar is phenyl, naphthyl orbiphenyl, each of which is unsubstituted or monosubstituted,disubstituted or trisubstituted by Hal, A, OH, NH₂, NO₂, CN, COOH,CONH₂, NHCOA, NHCONH₂, NHSO₂A, COH, SO₂NH₂, S(O)_(m)A, —(CH₂)_(n)—COOR²′or —O—(CH₂)_(o)—COOR²′, m and n are each, independently of one another,0, 1 or 2, o is 1, 2 or 3, T is piperidin-1-yl, pyrrolidin-1-yl,1H-pyridin-1-yl, morpholin-4-yl, piperazin-1-yl, 1,3-oxazolidin-3-yl,2H-pyridazin-2-yl, azepan-1-yl, 2-azabicyclo[2.2.2]octan-2-yl,pyrazol-2-yl, 1,3,4-thiadiazol-3-yl, imidazolidin-1-yl or1,2-dihydropyrazol-2-yl, each of which is monosubstituted or disubstituted by ═NR², ═N—CN, ═S or ═NOR² and may furthermore bemonosubstituted or disubstituted by A, CONH₂ or COOA, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios.
 23. Compounds of the formula Iaccording to claim 1, in which D is absent or is —CH═N—CH═CH—,—CH═CH—N═CH—, —NH—N═CH—, —CH═N—NH—, —O—N═CH— or —CH═N—O—, M is a phenylring, R¹ is H, CH₂NH₂, CONH₂, C(═S)NH₂ or NH₂, R¹′ is H, W iscyclohexanediyl, cyclopentanediyl, phenylene, biphenylene, furandiyl,thiophenediyl, pyrrolediyl, imidazolediyl, pyrazolediyl, oxazolediyl,isoxazolediyl, thiazolediyl, isothiazolediyl, pyridinediyl,pyrimidinediyl or pyrrolidinediyl, each of which is unsubstituted ormonosubstituted or disubstituted by R², R² is H or alkyl having 1, 2, 3,4, 5 or 6 carbon atoms, R²′ is H or alkyl having 1, 2, 3, 4, 5 or 6carbon atoms, X is CONH, CONHCH₂, CH₂NH or CH₂NHCH₂, Y is phenylenewhich is unsubstituted or monosubstituted or disubstituted by A, Br, Clor F, A is unbranched or branched alkyl having 1, 2, 3, 4, 5 or 6 carbonatoms and/or in addition 1-7H atoms may be replaced by F, T ispiperidin-1-yl, pyrrolidin-1-yl, 1H-pyridin-1-yl, morpholin-4-yl,piperazin-1-yl, 1,3-oxazolidin-3-yl, 2H-pyridazin-2-yl, azepan-1-yl,2-azabicyclo[2.2.2]octan-2-yl, pyrazol-2-yl, 1,3,4-thiadiazol-3-yl,imidazolidin-1-yl or 1,2-dihydropyrazol-2-yl, each of which is monosubstituted or di substituted by ═NR², ═N—CN, ═S or ═NOR² and mayfurthermore be monosubstituted or disubstituted by A, CONH₂ or COOA, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios.
 24. Compounds of the formula Iaccording to claim 1, in which D is absent or is —CH═N—CH═CH—,—CH═CH—N═CH—, —NH—N═CH—, —CH═N—NH—, —O—N═CH— or —CH═N—O—, M is a phenylring, R¹ is H, CH₂NH₂, CONH₂, C(═S)NH₂ or NH₂, R¹′ is H, W ispyrazolediyl or thiazolediyl, each of which is unsubstituted ormonosubstituted by A, X is CONH, Y is phenylene which is unsubstitutedor monosubstituted or disubstituted by A, Br, Cl or F, T is2-iminopyrrolidin-1-yl, 2-iminopiperidin-1-yl,2-imino-1,3,4-thiadiazol-3-yl, 2-iminoimidazolidin-1-yl or3-imino-1,2-dihydropyrazol-2-yl, and the corresponding hydroxyimino,cyanoimino, alkoxyimino and thioxo derivatives, where the heterocyclicradicals may furthermore be monosubstituted or disubstituted by A, CONH₂or COOA, A is unbranched or branched alkyl having 1, 2, 3, 4, 5 or 6carbon atoms and/or in addition 1-7H atoms may be replaced by F, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios.
 25. Compounds according toclaim 1 selected from the group consisting ofN-[4-(2-iminopyrrolidin-1-yl)phenyl]-2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[4-(2-thioxopyrrolidin-1-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[4-(2-methoxyiminopyrrolidin-1-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[4-(2-iminopyrrolidin-1-yl)phenyl]-2-(3-aminobenzo[d]isoxazol-5-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[4-(2-imino-5-methyl-3H-1,3,4-thiadiazol-3-yl)phenyl]-2-(3-aminobenzo[d]isoxazol-5-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[4-(1,5-dimethyl-3-imino-1,2-dihydropyrazol-2-yl)phenyl]-2-(3-aminobenzo[d]isoxazol-5-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[4-(2-thioxopyrrolidin-1-yl)phenyl]-2-(3-aminobenzo[d]isoxazol-5-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[4-(2-methoxyiminopyrrolidin-1-yl)phenyl]-2-(3-amino-1H-indazol-5-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[4-(2-thioxopyrrolidin-1-yl)phenyl]-2-(3-amino-1H-indazol-5-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[4-(2-methoxyiminopyrrolidin-1-yl)phenyl]-2-(3-thiocarbamoylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[4-(2-hydroxyiminopyrrolidin-1-yl)phenyl]-2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[3-methyl-4-(2-methoxyiminopyrrolidin-1-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[4-(2-iminopyrrolidin-1-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[3-bromo-4-(2-imino-5-methyl-3H-1,3,4-thiadiazol-3-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[4-(2-imino-5-methyl-3H-1,3,4-thiadiazol-3-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[4-(2-iminoimidazolidin-1-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[4-(2-iminoimidazolidin-1-yl)-3-methylphenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[4-(2-cyanoiminoimidazolidin-1-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[4-(2-cyanoimino-3-methylimidazolidin-1-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[4-(2-imino-5-ethyl-3H-1,3,4-thiadiazol-3-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[4-(2-imino-5-aminocarbonyl-3H-1,3,4-thiadiazol-3-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[4-(2-imino-5-ethoxycarbonyl-3H-1,3,4-thiadiazol-3-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxamide,N-[4-(2-imino-5-ethyl-3H-1,3,4-thiadiazol-3-yl)phenyl]-5-(3-aminocarbonylphenyl)-2-methylthiazole-4-carboxamide,N-[4-(2-imino-5-ethyl-3H-1,3,4-thiadiazol-3-yl)phenyl]-2-(3-aminocarbonylphenyl)-5-methyl-2H-pyrazole-3-carboxamide,and pharmaceutically usable derivatives, solvates and stereoisomersthereof, including mixtures thereof in all ratios.
 26. Process for thepreparation of compounds of the formula I according to claim 1 andpharmaceutically usable derivatives, solvates and stereoisomers thereof,characterised in that a) for the preparation of a compound of theformula I in which X is CONR² or CONR²C(R³)₂, a compound of the formulaII

in which L is Cl, Br, I or a free or reactively functionally modified OHgroup, and R¹, R¹′, D, M and W are as defined in claim 1, with theproviso that any further OH and/or amino group present is protected, isreacted with a compound of the formula IIIZ′-Y-T  III in which Z′ is NHR² or NHR²C(R³)₂, and R², Y and T are asdefined in claim 1, and any protecting group is subsequently removed, b)and/or in that a radical T, R¹ and/or R¹′ in a compound of the formula Iis converted into another radical T, R¹ and/or R¹′ by, for example, i)converting a sulfanyl compound into an imino compound, ii) removing anamino-protecting group, and/or a base or acid of the formula I isconverted into one of its salts.
 27. Compounds of the formula Iaccording to claim 1 as inhibitors of coagulation factor Xa. 28.Compounds of the formula I according to claim 1 as inhibitors ofcoagulation factor VIIa.
 29. Medicament comprising at least one compoundof the formula I according to claim 1 and/or pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and optionally excipients and/or adjuvants. 30.Medicament comprising at least one compound of the formula I accordingto claim 1 and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and atleast one further medicament active ingredient.
 31. Use of compoundsaccording to claim 1 and/or physiologically acceptable salts andsolvates thereof for the preparation of a medicament for the treatmentof thromboses, myocardial infarction, arteriosclerosis, inflammation,apoplexia, angina pectoris, restenosis after angioplasty, claudicatiointermittens, migraine, tumours, tumour diseases and/or tumourmetastases.
 32. Set (kit) consisting of separate packs of (a) aneffective amount of a compound of the formula I according to claim 1and/or pharmaceutically usable derivatives, solvates and stereoisomersthereof, including mixtures thereof in all ratios, and (b) an effectiveamount of a further medicament active ingredient.
 33. Use of compoundsof the formula I according to claim 1 and/or pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, for the preparation of a medicament for thetreatment of thromboses, myocardial infarction, arteriosclerosis,inflammation, apoplexia, angina pectoris, restenosis after angioplasty,claudicatio intermittens, migraine, tumours, tumour diseases and/ortumour metastases, in combination with at least one further medicamentactive ingredient.